Maternal use of selective serotonin reuptake inhibitors during pregnancy is associated with Hirschsprung’s disease in newborns – a nationwide cohort study

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Abstract

Background

Hirschsprung’s disease is a rare condition caused by congenital malformation of the gastrointestinal tract affecting 1:5000 children. Not much is known about risk factors for development of Hirschsprung’s disease. Two clinical cases of hirschsprung’s disease led to an investigation of the association between maternal use of selective serotonin reuptake inhibitors (SSRIs) during pregnancy and development of Hirschsprung’s Disease in the newborn child. The study examined a nationwide, unselected cohort of children born in Denmark from 1 January 1996 until 12 March 2016 ( n = 1,256,317). We applied multivariate models to register-based data to estimate the odds ratio of Hirschsprung’s disease, adjusting for possible confounders. The studied exposure period for SSRIs were 30 days prior to conception to the end of the first trimester.

Results

In the main exposed cohort the prevalence of Hirschsprung’s disease was 16/19.807 (0.08%) compared to 584/1.236.510 (0.05%) in the unexposed cohort. In women who redeemed a minimum of one prescription of selective serotonin reuptake inhibitors, the adjusted odds ratio for development of Hirschsprung’s disease was 1.76 (95%CI: 1.07–2.92). In women who redeemed a minimum of two prescriptions, the adjusted odds ratio for Hirschsprung’s disease was 2.34 (95% CI: 1.21–4.55).

Conclusions

Our data suggest that early maternal use of selective serotonin reuptake inhibitors is significantly associated with the development of Hirschsprung’s disease in the newborn child. Treatment of depression during pregnancy always has to be weighed against the risks posed by untreated maternal depression. Our results have to be confirmed in other studies.

Electronic supplementary material

The online version of this article (doi:10.1186/s13023-017-0667-4) contains supplementary material, which is available to authorized users.

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Most cited references 33

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The Danish Civil Registration System (CRS) was established in 1968, where all persons alive and living in Denmark were registered. Among many other variables, it includes individual information on personal identification number, gender, date of birth, place of birth, place of residence, citizenship, continuously updated information on vital status, and the identity of parents and spouses. To evaluate the quality and completeness of the information recorded on persons in the CRS, we considered all persons registered on November 4, 2005, i.e. all persons who were alive and resident in Denmark at least one day from April 2, 1968 to November 4, 2005, or in Greenland from May 1, 1972 to November 4, 2005. A total of 8,176,097 persons were registered. On November 4, 2005, 5,427,687 (66.4%) were alive and resident in Denmark, 56,920 (0.7%) were alive and resident in Greenland, 2,141,373 (26.2%) were dead, 21,160 (0.3%) had disappeared, and 528,957 (6.5%) had emigrated. Among persons born in Denmark 1960 or later the CRS contains complete information on maternal identity. Among persons born in Denmark 1970 or later the CRS contains complete information on paternal identity. Among women born in Denmark April 1935 or later the CRS contains complete information on all their children. Among males born in Denmark April 1945 or later the CRS contains complete information on all their children. The CRS contains complete information on: a) immigrations and emigrations from 1971 onwards, b) permanent residence in a Danish municipality from 1971 onwards, c) permanent residence in a municipality in Greenland from May 1972 onwards, and d) full address in Denmark from 1977 onwards. Data from the CRS is an important research tool in epidemiological research, which enables Danish researchers to carry out representative population-based studies on e.g. the potential clustering of disease and death in families and the potential association between residence and disease and death.

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5-Hydroxytryptamine (serotonin) in the gastrointestinal tract.

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The Genetics of Stress-Related Disorders: PTSD, Depression, and Anxiety Disorders.

Jordan W. Smoller (2016)

Research into the causes of psychopathology has largely focused on two broad etiologic factors: genetic vulnerability and environmental stressors. An important role for familial/heritable factors in the etiology of a broad range of psychiatric disorders was established well before the modern era of genomic research. This review focuses on the genetic basis of three disorder categories-posttraumatic stress disorder (PTSD), major depressive disorder (MDD), and the anxiety disorders-for which environmental stressors and stress responses are understood to be central to pathogenesis. Each of these disorders aggregates in families and is moderately heritable. More recently, molecular genetic approaches, including genome-wide studies of genetic variation, have been applied to identify specific risk variants. In this review, I summarize evidence for genetic contributions to PTSD, MDD, and the anxiety disorders including genetic epidemiology, the role of common genetic variation, the role of rare and structural variation, and the role of gene-environment interaction. Available data suggest that stress-related disorders are highly complex and polygenic and, despite substantial progress in other areas of psychiatric genetics, few risk loci have been identified for these disorders. Progress in this area will likely require analysis of much larger sample sizes than have been reported to date. The phenotypic complexity and genetic overlap among these disorders present further challenges. The review concludes with a discussion of prospects for clinical translation of genetic findings and future directions for research.

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Author and article information

Contributors

Sebastian Werngreen Nielsen: sebastian@werngreen.com

Perniller Møller Ljungdalh: pernille.ljungdalh@rsyd.dk

Jan Nielsen: JANNIE@RKKP.dk

Bente Mertz Nørgård: Bente.Noergaard@rsyd.dk

Niels Qvist: famqvist@dadlnet.dk

Journal

Journal ID (nlm-ta): Orphanet J Rare Dis

Journal ID (iso-abbrev): Orphanet J Rare Dis

Title: Orphanet Journal of Rare Diseases

Publisher: BioMed Central (London )

ISSN (Electronic): 1750-1172

Publication date (Electronic): 20 June 2017

Publication date PMC-release: 20 June 2017

Publication date Collection: 2017

Volume: 12

Electronic Location Identifier: 116

Affiliations

[1 ]ISNI 0000 0001 0728 0170, GRID grid.10825.3e, Department of Surgical Gastroenterology A, Odense University Hospital, and Research Unit of Surgery, Institute of Clinical Research, , University of Southern Denmark, ; 5000 Odense C, DK Denmark

[2 ]ISNI 0000 0001 0728 0170, GRID grid.10825.3e, Center for Clinical Epidemiology, Odense University Hospital, and Research Unit of Clinical Epidemiology, , University of Southern Denmark, ; 5000 Odense C, DK Denmark

[3 ]Engelshøjgade 26 1TH, 6400 Sønderborg, Denmark

Article

Publisher ID: 667

DOI: 10.1186/s13023-017-0667-4

PMC ID: 5477755

PubMed ID: 28633635

SO-VID: 62347607-bc7d-4c72-b124-bf7012786c31

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 2 March 2017

Date accepted : 12 June 2017

Funding

Funded by: PROCRIN

Award ID: R2-024

Award Recipient : Niels Qvist

Custom metadata

ScienceOpen disciplines: Infectious disease & Microbiology

Keywords: ssri,congenital malformation,hirschsprung’s disease,developmental biology,enteric nervous system,paediatric gastroenterology

Data availability:

ScienceOpen disciplines: Infectious disease & Microbiology

Keywords: ssri, congenital malformation, hirschsprung’s disease, developmental biology, enteric nervous system, paediatric gastroenterology

Maternal use of selective serotonin reuptake inhibitors during pregnancy is associated with Hirschsprung’s disease in newborns – a nationwide cohort study

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Most cited references 33

The Danish Civil Registration System. A cohort of eight million persons.

5-Hydroxytryptamine (serotonin) in the gastrointestinal tract.

The Genetics of Stress-Related Disorders: PTSD, Depression, and Anxiety Disorders.

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